Document Detail


STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients.
MedLine Citation:
PMID:  23454751     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types of cancer, including head and neck squamous cell carcinoma (HNSCC). In this study, we characterized CD14+HLA-DR(-/lo) cells sorted from the tumors, draining lymph nodes, and peripheral blood of HNSCC patients. CD14+HLA-DR(-/lo) cells were phenotyped as CD11b+, CD33+, CD34+, arginase-I+, and ROS+. In all 3 compartments, they suppressed autologous, antigen-independent T cell proliferation in a differential manner. The abundance of MDSC correlated with stage, but did not correlate with previous treatment with radiation or subsites of HNSCC. Interestingly, MDSC from all 3 compartments showed high phosphorylated STAT3 levels that correlated with arginase-I expression levels and activity. Stattic, a STAT3-specific inhibitor, and STAT3-targeted siRNA abrogated MDSC’s suppressive function. Inhibition of STAT3 signaling also resulted in decreased arginase-I activity. Analysis of the human arginase-I promoter region showed multiple STAT3-binding elements, and ChIP demonstrated that phosphorylated STAT3 binds to multiple sites in the arginase-I promoter. Finally, rescue of arginase-I activity after STAT3 blockade restored MDSC’s suppressive function. Taken together, these results demonstrate that the suppressive function of arginase-I in both infiltrating and circulating MDSC is a downstream target of activated STAT3.
Authors:
David Vasquez-Dunddel; Fan Pan; Qi Zeng; Mikhail Gorbounov; Emilia Albesiano; Juan Fu; Richard L Blosser; Ada J Tam; Tullia Bruno; Hao Zhang; Drew Pardoll; Young Kim
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-09     Completed Date:  2013-05-20     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1580-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Otolaryngology-Head and Neck Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21231, USA.
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD14 / metabolism
Arginase / genetics*,  metabolism
Carcinoma, Squamous Cell / enzymology*,  genetics,  pathology
Cell Proliferation
Cells, Cultured
Enzyme Repression
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
HLA-DR Antigens / metabolism
Head and Neck Neoplasms / enzymology*,  genetics,  pathology
Humans
Myeloid Cells / enzymology*,  pathology
Phosphorylation
Promoter Regions, Genetic
Protein Binding
Protein Processing, Post-Translational
RNA, Small Interfering / genetics
STAT3 Transcription Factor / genetics,  metabolism,  physiology*
Superoxides / metabolism
T-Lymphocytes / immunology,  physiology
Grant Support
ID/Acronym/Agency:
K23-DE018464/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD14; 0/HLA-DR Antigens; 0/RNA, Small Interfering; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 11062-77-4/Superoxides; EC 3.5.3.1/Arginase; EC 3.5.3.1/arginase I, human
Comments/Corrections

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